Presentation on theme: "Introduction of Clinical Trials"— Presentation transcript:
1Introduction of Clinical Trials Jessie ZhouDept.of Clinical Epidemiology and BiostatisticsMcMaster UniversityAugust 1, 2011
2Outline Overview of clinical trials History of the clinical trials Types of the clinical trialsDesign of the clinical trialsPhases of the clinical trialsSome issues on clinical trials design
3Overview of Clinical Trials What is Clinical TrialsAny form of planned experiment which involves patients and is designed to answer scientific questions and find better ways to prevent, diagnose, or treat disease.To discover or verify:Pharmaco dynamics (how it works)Pharmacokinetics (what happens to it)Therapeutic effects (Efficacy)Adverse reactions (Safety)
5Overview of Clinical Trials General thoughts:Study must examine valuable and important biomedical research questions.It must be based on rigorous methodology & It must follow strong ethical principles.The probability and magnitude of risk – benefit to the participants.The population to be studied – its Size, Availability and Accessibility.
6Overview of Clinical Trials Some examples:Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.g., patients who have been diagnosed with Alzheimer's disease)Assess the safety and effectiveness of a different dose of a medication than is commonly used (e.g., 10 mg dose instead of 5 mg dose)Assess whether the new medication or device is more effective for the patient's condition than the already used, standard medication or device ("the gold standard" or "standard therapy“)
7History of Clinical Trials The history of clinical trials before 1750 is briefThe first reference - King Nebuchadnezzar IIPersian scientist Ibn Sina wrote Canon of Medicine around the 10th centuryOne of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvyFrederick Akbar Mahomed (1884), made substantial contributions to the process of clinical trialsseparated chronic nephritis with secondary hypertension from what we now term essential hypertensionfounded "the Collective Investigation Record for the British Medical Association
8History of Clinical Trials From 1800 onwards, more attention was paid to study design.Placebos were first used in 1863.The idea of randomization was introduced in 1923In 1930, the US Food and Drug Administration (FDA) was found.The first trial using properly randomized treatment and control groups was carried out in 1948Since 1945, the ethical impact of clinical trials has become increasingly importantClinical trials have thus evolved into a standard procedure, focusing on patient safety and requiring informed consent from all participants.
9Types of Clinical Trials By type of productsPharmaceutical Products (Synthetic “Drugs”)Biotechnology Products (products made from human cells/tissues for example, such as vaccines, blood products)Devices (e.g., cardiac stents, pacemakers)
10Types of Clinical Trials By purpose of the trialsTreatment trialsPrevention trialsEarly-detection trials/screening trialsDiagnostic trialsQuality-of-life studies/supportive care studies
11Types of Clinical Trials By the way of research behaveTreatment studiesRandomized controlled trialNonrandomized trial (quasi-experiment)Observational studiesCohort studyCase-control studyCross-sectional studyEcological study
12Phases of Clinical Trials Pre-Clinical (in vivo, in vitro)Phase I - Safety & Early Clinical PharmacologyPhase II - Initial Efficacy & Safety.Phase III - Comprehensive Efficacy & SafetyPhase IV - Post Marketing surveillance Studies
13Phase I Clinical Trials First time in humansObjectivesAssess pharmacology/pharmacokineticsHow drug flows through bodyHow drug is excreted and how long (half-life)Assess toxicology (safety)Adverse events, Labs, EKGs, Vital Signs, Physical ExamsDetermine maximum tolderated dose (MTD)Performed usually in subjectsNo interest in efficacyDescriptive Analysis
14Phase II Clinical Trials Performed in usually patientsSample often based on time, cost considerationsConcentrate on safety, but also look at efficacyOften exploratory in terms of efficacyFind parameters on which product is efficacious?Find magnitude of the product’s effect on these parameters?Contains control group (placebo/active)
15Phase II Clinical Trials Multiple dosesFind dose with best safety profile and best efficacy profile (not always the highest dose)Use results to design confirmatory Phase III trialsNot necessarily required to obtain statistical significance (“p<0.05”) in Phase II in order to move to Phase III
16Phase III Clinical Trials ObjectiveConfirm efficacy of new drug seen in Phase IIDetermine safety of new drug (especially for uncommon “adverse events”).Often called “Pivotal” trials
17Phase III Clinical Trials Often performed in 2 treatment groupsStudy drug vs. ControlControl may be Active or PlaceboSome suggest both Active and Placebo controlIf Active-controlled, not necessary to show superiority, but “non-inferiority” or “equivalence”FDA has no official rules about control group
18Phase III Clinical Trials Sample size based heavily on statisticsIf treatment works in population, we want a sample large enough to represent populationi.e., Want a high probability treatment works in sampleFDA usually requires 2 phase III studies, with p<0.05 for efficacy (if superiority trial)For “large simple trials” only one large study may suffice (with, say, p<0.01 or p<0.001).
19Phase II/III Clinical Trials Phase IIb, Phase II/III TrialsExploratory, but less so than Phase IIState a specific analysis; if successful, consider study as one of the Phase IIIs (“pivotal”)If not successful, then consider as exploratory analysis for planning Phase III
20Phase IV Clinical Trials Post Marketing Surveillance TrialInvolve the safety surveillance (pharmacovigilance) and ongoing technical supportRequired by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasonsDetect any rare or long-term adverse effects over a much larger patient population and longer time periodPhase IV trials may result in a drug being no longer sold (Harmful effects)
21Design of Clinical Trials Study objectiveStudy designSample sizeRandomizationAllocation concealmentBlinding
22Study objectiveResearcher and statistician should jointly articulate the objective of the study.The objective should be clearly defined.Ex: While drug “X” was testing for hypertension, the bald head patients reported hair growth. (Minoxidil)In the above situation, the researcher and statistician may get confusion while collecting the data
23Study design Descriptive studies Analytical studies Case reports Case seriesPopulation studiesAnalytical studiesSurveyObservationalExperimental
24Descriptive Studies Case report Case series Population studies A method designed to give a detailed description of a single caseCase seriesA method designed to give a detailed description of more than one casePopulation studiesThis is the observation of a defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously.
25Descriptive Studies: Uses Health care planningEducation or prevention and allocating resources more efficiently.Hypothesis generationSearching for determinants or risk factors that can be altered or eliminated to reduce or prevent disease.Trend AnalysisSuggesting associations
26Analytical studies Survey It involves measuring a set of parameters in a population group or in a sample of subjects.It is usually performed with a carefully developed and pre tested QUESTIONNAIRE.Most effective for estimation of the frequency of parameters
32Analytical studies Experiment design Simple experiment design Subjects assigned as two groups.Treatment group & Control (or placebo) group.Treatment assigned to treatment group and no treatment or placebo assigned to control group.The outcome measures are compared at the end of experiment.
33Analytical studies Experiment design Parallel group design * A homogenous group of subjects is selected then subjects are randomly allocated into treatment & control groups.Ex: Total population = male + femaleThen the male & female subjects were separated as individual/parallel groups.* Disadvantage: Inter-subject variation is not being correlated.
35Analytical studies Experiment design Repeated measures design * Same as the simple experiment, but the repeated measures were taken in both, the treatment group as well as the control group.* Here the results are some more accurate than simple experiments.
36Analytical studies Experiment design Crossover design * Get two or more treatments successively.* Time gap - “WASH OUT PERIOD”.* This method minimizes the “inter-subject variation”; some more accurate than simple experiments.* Requires less no. of subjects to get meaningful results.* But the only disadvantage is, increased no. of study periods leads to subject drop outs & longer duration.
37Analytical studies Experiment design Factorial design A DRUG Level A=0 * To estimate the effect of main treatment & other factors simultaneously.* In a specific case of 2 treatments A & B,* The groups taken as:Given neither A (A=0) nor B (B=0)Given A alone (A=1) & not B (B=0)Given B alone (B=1) & not A(A=0)Given both A (A=1) & B (B=1)ADRUGLevelA=0A=1BNoneA aloneB aloneA&B bothB=0B=1
38Sample SizeIf few subjects were chosen, it may not give accurate outcome / the results are not trusty.If large no. of subjects were taken, then the time span and cost of the study will increases highly.But “Unfortunately there is no way of guaranteeing an adequate sample size”.The experienced investigator can only make an educated guess about the suitable adequate sample size.
39Sample Size How to guess Study objectives and hypothesis Type I error and Type II errorPrecision analysisPower analysis
40RandomizationThe probability that allows every subject to get equal treatment.To minimize or avoid bias and errors.Randomization techniques:Simple randomizationblocked randomizationStratified randomizationFactorial randomization
41Randomization Simple randomization Like “different color balls drawn from a basket”.First the subjects satisfying selection criteria are identified.Later, from the above group subjects are chosen in random manner.
43Randomization Blocked randomization number of subjects in one group versus the other group are specified, and subjects are allocated randomly within each block..
44Randomization Stratified randomization First all the subjects are divided into 2 specific groups (STRATA) on the basis of some predefined factor. So, 2 or more “Stratas” will formed.Later, from the individual strata, the random samples will be taken& assigned as study groups.
46Randomization Factorial randomization Ex: Comparison of response pattern with two treatments in depressed as well as non depressed male and female subjects.Randomize subjects from each type.Male – DepressedMale – Non depressedFemale – DepressedFemale – Non depressed
47FACTORIAL RANDOMIZATIO SEXFACTORSMALEFEMALEA B A BDISEATNON DEPRESSEDDEPRESSED
48Allocation concealment Protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the studysequeBlindingntially-numberedopaquesealed envelopes (SNOSE)sequentially-numbered containerspharmacy controlled randomizationcentral randomization
49Blinding Types of studies on the basis of blinding: Open/ No blinding: Investigator, patient & statistician all are aware of treatmentSingle blindOne party, either the patient or the investigator aware of treatment. (Mostly the investigator will be aware.)Double blind:Neither the investigator nor the patient are aware of treatment.Triple blindInvestigator, subject and the statistician is also not aware of treatment
50Blinding Methods of achieving double blinding: If two treatments are available in the form of tablets then matching both tablets in terms of colour/shape/size.If two treatments available in different forms like tablet(A) & capsule(B), then all subjects are given both 1tablet & 1capsule.Here subjects assigned to treatment “A” will get original drug containing tablet and a placebo capsule.Subjects assigned to treatment “B” will get original drug containing capsule and a placebo tablet.